Discovery of a Flavonoid FM04 as a Potent Inhibitor to Reverse P-Glycoprotein-Mediated Drug Resistance in Xenografts and Improve Oral Bioavailability of Paclitaxel

• Published in: International journal of molecular sciences Vol. 23; no. 23; p. 15299
• Main Authors: Kan, Jason W Y, Yan, Clare S W, Wong, Iris L K, Su, Xiaochun, Liu, Zhen, Chan, Tak Hang, Chow, Larry M C
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.12.2022; MDPI
• Subjects: ABC transporters; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Bioavailability; Biotransformation; Cancer therapies; Chemotherapy; Clinical trials; Drug resistance; Drug Resistance, Neoplasm; Drugs; Flavonoids; Flavonoids - pharmacology; Glycoproteins; Humans; Inhibitors; Intestinal absorption; Intestine; Liver; Melanoma; Melanoma - drug therapy; Metabolism; Metabolites; Mice; modulator; Molecular weight; multidrug resistance; Oral administration; oral bioavailability; P-Glycoprotein; Paclitaxel; Physicochemical properties; Polyethylene glycol; Substrates; Toxicity; Tumors; Xenografts; Xenotransplantation; P-glycoprotein; multidrug resistance; modulator; flavonoids; oral bioavailability
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232315299

Biotransformation of flavonoid dimer FD18 resulted in an active metabolite FM04. It was more druggable because of its improved physicochemical properties. FM04 (EC50 = 83 nM) was 1.8-fold more potent than FD18 in reversing P-glycoprotein (P-gp)-mediated paclitaxel (PTX) resistance in vitro. Similar to FD18, FM04 chemosensitized LCC6MDR cells towards multiple anticancer drugs by inhibiting the transport activity of P-gp and restoring intracellular drug levels. It stimulated the P-gp ATPase by 3.3-fold at 100 μM. Different from FD18, FM04 itself was not a transport substrate of P-gp and presumably, it cannot work as a competitive inhibitor. In the human melanoma MDA435/LCC6MDR xenograft, the co-administration of FM04 (28 mg/kg, I.P.) with PTX (12 mg/kg, I.V.) directly modulated P-gp-mediated PTX resistance and caused a 56% (*, p < 0.05) reduction in tumor volume without toxicity or animal death. When FM04 was administered orally at 45 mg/kg as a dual inhibitor of P-gp/CYP2C8 or 3A4 enzymes in the intestine, it increased the intestinal absorption of PTX from 0.2% to 14% in mice and caused about 57- to 66-fold improvement of AUC as compared to a single oral dose of PTX. Oral co-administration of FM04 (45 mg/kg) with PTX (40, 60 or 70 mg/kg) suppressed the human melanoma MDA435/LCC6 tumor growth with at least a 73% (***, p < 0.001) reduction in tumor volume without serious toxicity. Therefore, FM04 can be developed into a novel combination chemotherapy to treat cancer by directly targeting the P-gp overexpressed tumors or potentiating the oral bioavailability of P-gp substrate drugs.